Chronic Kidney Disease

@ckd_ce on Twitter

1) Welcome to a new #accredited #tweetorial regarding evaluation of mechanism of action and potential for therapeutics from combining endothelin type A antagonists and angiotensin II type 1 receptor blockers. Leading us through this material is @didemturgut_ from Turkey ๐Ÿ‡น๐Ÿ‡ท

2) This tweetorial is accredited for 0.5h CE/#CME for #physicians #nurses #NPs #PAs #pharmacists ๐Ÿ‡บ๐Ÿ‡ธ๐Ÿ‡จ๐Ÿ‡ฆ๐Ÿ‡ช๐Ÿ‡บ๐Ÿ‡ฌ๐Ÿ‡ง. Please follow along! Faculty disclosures are at https://ckd-ce.com/disclosures/, and past programs, still available for credit, are at https://ckd-ce.com/. All ๐Ÿ†“!!

3) This educational program is supported by grants from Travere, Bayer, & Otsuka, and is intended for healthcare providers.

4) Letโ€™s start with the historical review of the #endothelin receptor antagonists. In the early 1988 Yanagisawa et al isolated an endothelium-derived 21-residue vasoconstrictor peptide endothelin (#ET), and the journey started. See ๐Ÿ”“

https://pubmed.ncbi.nlm.nih.gov/2451132/
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5) In the 21 years since its discovery, ET shown to be one of the most potent #vasoconstrictors known. In mammals, the ET family comprises three endogenous isoforms–ET-1, ET-2 & ET-3–and the receptors that mediate their effects. See https://pubmed.ncbi.nlm.nih.gov/15063086/.

6) ET peptides and ET receptors have been localized to a wide number of tissues and organs. It comes as no surprise that ET has been targeted as a pathophysiological culprit in multiple diseases and/or conditions.

7) There are at least four known ET receptors among the isoforms:, ETA, ETB1, ETB2 and ETC. Explained well in https://www.amazon.com/Medical-Physiology-2e-Updated-PHYSIOLOGY/dp/1437717535. +

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8) In human vessels, ETA receptors are mainly located on vascular smooth muscle cells and are mainly responsible for contraction, with ETB receptors being present on endothelial cells lining the vessel wall.

9) ET stimulates proliferation in different cell types (mainly via the ETA receptor) and thought to be co-mitogenic, potentiating the actions of other growth factors. See ๐Ÿ”“https://pubmed.ncbi.nlm.nih.gov/25421754/.

11) The answer may surprise you!
As per ๐Ÿ”“https://www.seminarsinnephrology.org/article/S0270-9295(15)00028-5/fulltext, Although while measurements of receptors within smooth muscle throughout the renal vasculature show a predominance of ETA, 70% of the ET receptors in both cortex and medulla in human kidney are ETB.

12) But wait–there is another surprise!
#ETA have been shown to be present on human and rat #podocytes. In renal disease, proliferation in mesangial cells, extracellular matrix production, and inflammation are mediated mainly by ETA.
๐Ÿ”“

https://www.sciencedirect.com/science/article/pii/S0925443910000712
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13) Till tomorrow, think about the potential effects of #ETA and #ETB on the kidney, and potential therapeutic consequences if we control these receptors. Exciting! ๐Ÿ‘#FOAMed #medtwitter #nephtwitter @MedTweetorials @TurkNefro @NephrolSocTurk @VijayanMD @priti899 @deniise_am

14) Welcome back! We are providing foundational knowledge on potential for therapeutics that combine antagonists of #endothelin type A & #angiotensin2 type 1 receptors. And YOU are earning CE/#CME! I am @didemturgut_ ๐Ÿ‡น๐Ÿ‡ท Welcome, @kidneydoc101 @goKDIGO @anace710 @AnandhUrmila

15) Letโ€™s start the day with the drugs antagonizing #ET receptors.

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16) They are designed as either ETA-selective antagonists (with an ETA/ETB selectivity ratio > 100) or dual ETA/ETB antagonists. Only a few ETB-selective antagonists have been developed, and these have never reached clinical use. See ๐Ÿ”“

https://www.mdpi.com/2077-0383/9/3/824/htm

17) Which of the ET receptor antagonists work for kidney diseases, by which receptor blockage?
a) Atrasentan via ETB
b) Sparsentan via ETB
c) Sparsentan via ETA +ARB
d) Sitaxsentan via ETA/ETB
ANSWER BEFORE YOU SCROLL โคต๏ธ!

18) The answer is c. ETA blockers are predominantly studied in the kidney diseases. Again see ๐Ÿ”“

https://www.mdpi.com/2077-0383/9/3/824/htm

19) Within the kidney, #ETB receptors activation lowers #bloodpressure by promoting #natriuresis & #diuresis by directly inhibiting reabsorption of sodium & water in the #nephron.

20) This suggests that an ETA-selective antagonist could have more beneficial effects than the mixed #ETA and #ETB antagonism in #kidneydiseases. See ๐Ÿ”“

https://pubmed.ncbi.nlm.nih.gov/24805108/

21) Since the kidneys are master chef of the #RAAS, ET becomes the provocative factor for the system. ET-1 โฌ†๏ธthe formation of ANG II by โฌ†๏ธing activity of angiotensin-converting enzyme.

22) ANG II then activates renal ET-1 production โžก๏ธvasoconstrictor positive feedback loop. ๐Ÿ”“

23) Dual therapy for the first time was studied in 1998. ETA receptor antagonist & #trandolopril combination decreased proteinuria prominently in rats with #Heymann nephritis. See ๐Ÿ”“

https://pubmed.ncbi.nlm.nih.gov/9690201/

24) The 1โƒฃst clinical study with dual therapy was in diabetic nephropathy #DKD. It was relevant that addition of ERAs to a standard nephro-protective therapy with #RAASi โžก๏ธ additional benefits in treatment of progressive diabetic nephropathy. ๐Ÿ”“

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653691/

26) The main clinical concern associated with ERAs are dose-related oedemas. But . . . ERAs may induce #headache, #angioedema & #hypotension; sulfonamide-based ERAs may cause #hepatotoxicity. ERAs, similar to RAAS inhibitors are teratogenic. ๐Ÿ”“

https://pubmed.ncbi.nlm.nih.gov/24805108/

27) Tomorrow we'll continue on to ETA receptor antagonists & the DUAL endothelin angiotensin receptor antagonists #DEARAs. COME BACK! For a sneak peek, u can also see (& earn MORE ๐Ÿ†“CE/#CME) at https://ckd-ce.com/foundations-deara/ from @HecmagsMD!
@GoggleDocs @edgarvlermamd @nephondemand

28) Welcome back! I am @didemturgut_ & today we'll wrap up this #tweetorial on the eval of mechanism of action & potential for tx from combining endothelin type A antagonists w/angiotensin II type 1 receptor blockers. So as to clinical trials related to ERAs in #KidneyDisease:

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29) Urinary ET-1 excretion, which reflects renal ET-1 production, is โฌ†๏ธin every cause of CKD in which it has been studied, including #diabetes, #hypertension, #glomerulonephritis, #PCKD, & others. See https://pubmed.ncbi.nlm.nih.gov/9002526/.

30) The effects of acute intravenous administration of ERAs on #CKD patients have investigated in a series of very nice studies.

Im Ready Lets Go GIF by Travis

31) For example: after administration of BQ-123 (ETA receptor antagonist), theโฌ‡๏ธ in proteinuria & pulse wave velocity was greater in those subjects receiving dual ACE-I/ARB treatment than in those on ACE-I alone. Patients were nondiabetic #CKD patients.

https://pubmed.ncbi.nlm.nih.gov/19652085/

32) Data suggesting that ETA blockade in #CKD may be most effective in the setting of maximal #RAAS blockade provided insight into the use of dual therapies to be used immediately in trials with #CKD or #DKD.

33) In the ASCEND study, avosentan decreased ACR after a median follow-up of 4 months. Patients were on optimal RAS blockade. However the trial was prematurely terminated due to adverse cardiovascular events in the avosentan groups. See ๐Ÿ”“https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831858/.

34) It was hypothesized that at the higher doses, avosentan may act on the ETB receptor to promote additional fluid retention. Given the failure of the ASCEND trial, subsequent trials examining ERAs in kidney diseases were undertaken w/very careful ERA dose & patient selection.

35) In the RADAR study, a subsequent Ph 2b trial of 211 patients with #T2D on #RAASi with #eGFR 30โ€“75 ml/min/1.73m2 & #UACR 300โ€“3500 mg/g, atrasentan (0.75 or 1.25 mg/day) reduced UACR over 12 weeks by ~ 36% at either dose. See ๐Ÿ”“https://pubmed.ncbi.nlm.nih.gov/24722445/.

36) Encouraged by RADAR, the Ph 3 Study of Diabetic Nephropathy with Atrasentan (SONAR, https://pubmed.ncbi.nlm.nih.gov/30995972/) was conducted in adults with T2D, eGFR 25โ€“75 ml/min/1.73 m2, & UACR 300โ€“5000 mg/g who were receiving maximal tolerated dose of RAASi.

37) The important lessons from #SONAR were:
๐Ÿ‘‰ #Atrasentan significantly reduced renal events in type 2 diabetes.
๐Ÿ‘‰ Atrasentan did not alter composite major cardiovascular outcomes
๐Ÿ‘‰ It did reduce nonfatal stroke

38) The idea of combining structural elements of RAS (AT1) & ETA antagonistsโžก๏ธdual endothelin angiotensin receptor antagonist (#DEARA). #Sparsentan is a first-in-class, orally active DEARA w/similar high affinity to both receptors.

39) Its mechanism of action is based on structural similarities with #irbesartan and some ETA receptor antagonists. See ๐Ÿ”“https://pubmed.ncbi.nlm.nih.gov/27009050/.

41) It's ALL! *7โƒฃ* Ph 1 clinical studies in healthy volunteers & 2 Ph 2 studies in pts w/essential #hypertension but not yet published. Focus was not on proteinuria but on #HTN, where effects stronger than those of irbersartan. https://pubmed.ncbi.nlm.nih.gov/14718594/; ๐Ÿ”“

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896079/

42) Subsequently, clinical trials have been conducted to assess efficacy & safety of #sparsentan in different #glomerulopathies. See again

https://publicum.umed.lodz.pl/info.seam?id=AML7dc22144b4d34d6489d6d0104bba46c1

43) And as u learned from @HecmagsMD while u earned CE/#CME at https://ckd-ce.com/foundations-deara/, the journey is only beginning. New studies of #sparsentan are currently enrolling. #SPARTAN (https://clinicaltrials.gov/ct2/show/NCT04663204): pts w/bx-proven #IgAN but no #RAASi will be treated with sparsentan . . .

44) … for 110 weeks to assess its #nephroprotective potential. In #PROTECT (https://clinicaltrials.gov/ct2/show/NCT03762850), same goal but by comparing long-term (2 yrs) impact of sparsentan vs an #ARB. And there's a pediatric study, https://clinicaltrials.gov/ct2/show/NCT05003986

45) … with selected #proteinuric #glomerular diseases such as #FSGS, Minimal Change Disease #MCD, #IgAN, Immunoglobulin A-Associated #Vasculitis, & #Alport Syndrome

46) The limited current treatment options in kidney diseases indicate a compelling need to develop an effective and safe nephroprotective therapy. As preliminary results from clinical trials are encouraging, sparsentan could become one of these therapies.

47) And so you have made it! ๐Ÿ†“CE/#CME! #Physicians #pharmacists #nurses #PAs: go to https://ckd-ce.com/foundations_deara2/ and claim your credit! I am @didemturgut_ . Follow @ckd_ce (& @cardiomet_CE) for more #tweetorials! #medtwittter #nephtwitter #FOAMed

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Originally tweeted by @CKD_ce (@ckd_ce) on May 3, 2022.